Alzheimer's disease is a familiar chronic neurodegenerative disease, which is clinically expressed as progressive hypomnesia and cognitive disorder, and final loss of self-care ability, and is pathologically characterized by the occurrence of neurofibrillary tangle inside nerve cells and extracellular senile plaque. The principal components of senile plaque include a series of β-amyloid peptides, Aβ, having various lengths.
Aβ is a polypeptide containing 39 to 43 amino acids, and is derived from β-amyloid precursor protein, β-APP. There are two routes for cleavage of β-APP in vivo: non-amyloid route and amyloid route. Non-amyloid route refers to cleavage of β-APP with α-secretase, γ-secretase, without resulting in Aβ. Amyloid route refers to cleavage of β-APP at N-terminal with β-secretase, to form β-CTF (C-terminal fragments) including entire Aβ sequence, followed by cleavage of β-CTF with γ-secretase to result in Aβ.
β-secretase belongs to Asp protease, and is also called as BACE1, Asp2 or Memapsin-2 (Sinha S, Anderson J P, Barbour R, et al: Nature, 1999, 402(6761): 537-540). Due to disequilibrium of production and metabolism, dissociation and aggregation of Aβ, an abnormal amount of Aβ gradually aggregates to form senile plaque, which subsequently leads to pathological changes including neurofibrillary tangle, microgliocyte inflammation, neuron apoptosis, neurotransmitter deficiency and etc., and finally results in senile dementia. β-Secretase is a rate-limiting enzyme for producing Aβ. Thus, it is possible to prevent or treat Alzheimer's disease by inhibiting the activity of β-secretase to decrease or block the production of Aβ, to thereby reduce the content of Aβ, and prevent aggregation of Aβ in brain which leads to the formation of senile plaque (Hardy J, Dennis D J. Science, 2002, 297:353-356). Meanwhile, it is also possible to prevent or treat other diseases such as amyloid degenerative angiopathy, Kuru's disease and Down's syndrome induced by aggregation or deposition of Aβ.
BACE1 gene knock-out mouse had no production of Aβ in brain, and lived substantially normally, which further demonstrated that it was possible to prevent or treat diseases induced by aggregation or deposition of Aβ, in particular neurodegenerative diseases such as Alzheimer's disease, by blocking the production of Aβ, while, as presumed, would not result in much great side effect (Roberds S L, Anderson J, Basi G, et al: Hum Mol Genet, 2001, 10(12): 1317-1324).